rs749849931

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2

The NM_017752.3(TBC1D8B):c.104_106dupGGG(p.Gly35dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000192 in 1,207,057 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 65 hem. )

Consequence

TBC1D8B
NM_017752.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.43

Publications

0 publications found

Variant links:

Genes affected

TBC1D8B (HGNC:24715): (TBC1 domain family member 8B) This gene encodes a protein with a TBC (Tre-2/Bub2/CDC16) domain. Some mammalian proteins with this domain have been shown to function as Rab-GAPs by binding to specific Rab proteins and affecting their GTPase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

TBC1D8B Gene-Disease associations (from GenCC):

nephrotic syndrome, type 20
Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TBC1D8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_017752.3. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000188 (21/111682) while in subpopulation NFE AF = 0.00032 (17/53055). AF 95% confidence interval is 0.000203. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3 link	c.104_106dupGGG	p.Gly35dup	disruptive_inframe_insertion	Exon 1 of 21	ENST00000357242.10	NP_060222.2	Q0IIM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D8B	ENST00000357242.10 link	c.104_106dupGGG	p.Gly35dup	disruptive_inframe_insertion	Exon 1 of 21	1	NM_017752.3	ENSP00000349781.5	Q0IIM8-1
TBC1D8B	ENST00000310452.6 link	c.104_106dupGGG	p.Gly35dup	disruptive_inframe_insertion	Exon 1 of 12	1		ENSP00000310675.2	Q0IIM8-3
TBC1D8B	ENST00000481617.6 link	c.104_106dupGGG	p.Gly35dup	disruptive_inframe_insertion	Exon 1 of 7	1		ENSP00000421375.1	D6RFZ2
TBC1D8B	ENST00000276175.7 link	c.104_106dupGGG	p.Gly35dup	disruptive_inframe_insertion	Exon 1 of 21	5		ENSP00000276175.3	J3KN75

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000152

AC:

AN:

177933

AF XY:

0.000189

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000737

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000193

AC:

211

AN:

1095375

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

361049

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.0000570

AC:

AN:

35077

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19256

East Asian (EAS)

AF:

0.00

AC:

AN:

30125

South Asian (SAS)

AF:

0.00

AC:

AN:

53706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39835

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3991

European-Non Finnish (NFE)

AF:

0.000238

AC:

200

AN:

841029

Other (OTH)

AF:

0.000196

AC:

AN:

45977

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000188

AC:

AN:

111682

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33890

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30732

American (AMR)

AF:

0.000284

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6067

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53055

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000204

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 20

Uncertain:1

Feb 06, 2025

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as VOUS. Following criteria are met: PM4_Supporting -

not provided

Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.104_106dup, results in the insertion of 1 amino acid(s) of the TBC1D8B protein (p.Gly35dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749849931, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TBC1D8B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2072366). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.4

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs749849931

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over